Translation of Pro-Angiogenic and Anti-Angiogenic Therapies into Clinical Use - Mechanical and Chemical Signaling in Angiogenesis - page 262

3.2 FGF Cytokines for Therapeutic Angiogenesis
The pro-angiogenic FGF cytokines have also been investigated for therapeutic
angiogenesis of myocardial ischemia. In canine models of acute myocardial
infarction, the intrapericardial injection of basic fibroblast growth factor (FGF2)
induced angiogenesis in the infarcted area [ 46 ]. The result of FGF2 treatment was
improved cardiac systolic function and reduced infarct size. Therapies based on
FGF have subsequently been evaluated in clinical trials, with limited success. The
AGENT (Angiogenic Gene Therapy) trial evaluated the safety of intracoronary
delivery of an adenovirus encoding FGF4 [ 47 ]. Seventy-nine patients with
coronary artery disease were randomized to receive a placebo or FGF4 adenovirus;
the treatment was demonstrated to be safe. A phase II trial, the AGENT-2 study,
then examined whether the FGF4 adenovirus treatment could improve myocardial
perfusion [ 48 ]. In this randomized controlled double-blind trial, 52 patients with
coronary artery disease were randomized to receive a placebo or FGF4 gene
therapy. After 8 weeks, patients who received intracoronary injections of FGF4
gene therapy showed a significant reduction in ischemic defect size.
Two subsequent clinical trials, the AGENT-3 and AGENT-4 trials, were
initiated as phase III studies of the FGF4 adenovirus for myocardial ischemia [ 49 ].
The two trials enrolled a total of 532 patients with coronary artery disease who
were unsuitable for mechanical revascularization; both trials were randomized,
double-blinded, and placebo-controlled. Patients were randomized to receive
placebo, a low dose of FGF4 gene therapy, or a high dose of FGF4 gene therapy.
The trials were intended to last 12 weeks. However, both trials were halted early,
when an interim analysis revealed that the trials would fail to meet the primary
endpoint: there would be no statistical significance between treatment groups in
exercise treadmill time at 12 weeks.
There are several possible explanations for the failure of therapeutic angiogen-
esis utilizing VEGF or FGF in large-scale clinical trials. In terms of
pharmacokinetics, VEGF and other growth factors have a relatively short half-life in
the blood [ 50 ]; this may limit the ability of cytokines to act on target tissues. In terms
of clinical trial design, the dosing concentrations and dosing schedules may have
been suboptimal, and the routes of administration may have been ineffective [ 51 ]. In
terms of cytokine biology, each cytokine has multiple physiological effects.
Moreover, physiological angiogenesis involves the coordinated effort of multiple
pro-angiogenic molecules. A single pro-angiogenic factor may be insufficient for
lasting induction of angiogenesis. Therapeutic regimens that utilize combinations of
cytokines may be required to achieve a clinically meaningful effect. Finally in terms
of disease pathology, patients with coronary artery disease are likely to exhibit
endothelial dysfunction, particularly in the context of severe atherosclerotic disease.
This cellular dysfunction could limit the efficacy of therapeutic angiogenesis [ 52 ].
Novel biomaterials for therapeutic delivery could improve the clinical efficacy
of pro-angiogenic therapies. Drug delivery vehicles may be useful for targeting
cytokines to diseased tissue, thereby increasing the effective concentration of